The central theme of this PPG is that exercise training (EX) is beneficial in treating of and blunts development of coronary heart disease (CHD) by beneficial alterations in function and phenotype of coronary smooth muscle (CSM) and endothelial cells. We have 3 major goals: 1) Elucidate cellular/molecular mechanisms regulating CSM and endothelium; 2) Determine mechanisms of EX-induced changes in control of vascular resistance and permeability; and 3) Apply understanding of vascular biology and mechanisms of adaptation to models of CHD (diet induced hyperlipidemia). Our work reveals important features of EX-induced alterations in coronary function at tissue and cellular/molecular levels. We will test hypotheses concerning these adaptive mechanisms with an integrated experimental approach examining function throughout the coronary tree. The first project tests the hypothesis that EX increases the number and/or activity of CSM L-type VGCCs, and that increased tone is caused by interactions of Ca influx and K currents in EX-CSM. Project 2 tests the hypothesis that EX alters CSM receptor signaling mechanisms of adenosine (ADO) and endothelin-1 (ET-1) and alters CSM ADO transporters and thereby ADO mechanisms of adenosine (ADO) and endothelin-1 (ET-1) and alters CSM ADO transporters and thereby ADO sensitivity via metabolism and receptor regulation of K channels. Project 3 tests the hypothesis that EX increases expression of genes coding for endothelium-derived mediators and vascular antioxidant systems and that artery size, location, and mechanical forces influences the effects of EX on endothelial phenotype. Project 4 tests the hypothesis that NO- dependent mechanisms underlie ADO-induced increases in permeability and exchange following EX and will test hypotheses concerning structures forming exchange barrier in coronary microvessels, and the signaling mechanisms involved. We will continue accomplishing our goals with close collaborations among investigators. Our multi-faceted approach incorporating molecular, biochemical, cellular, pharmacologic, and physiologic techniques in pigs, coronary vessels, single cells and subcellular components is unique in exercise science. This research will advance understanding of cellular/molecular mechanisms for coronary adaptations and likely reveal new and/or improved methods for prevention and treatment of CHD.